In response to a decrease in plasma glucose concentration, endogenous glucose production (EGP) is stimulated through hormonal signals and also via non-hormonal or "autoregulatory" mechanisms. It has been well established that the hormonal response to hypoglycemia is impaired in persons with type 1 diabetes, and recent data from our laboratory suggest that the non-hormonal component of activation of EGP may also be defective. The present proposal is designed to examine a potential mechanism for this activation and to compare the effect of acute hypoglycemia on EGP in nondiabetic vs. type 1 diabetic (DM1) individuals at plasma glucose levels above the threshold for activation of counterregulatory hormones. Our data taken together with the literature suggest that an hepatic "autoregulatory" mechanism may operate at the level of the glucose-6-phosphate pool in response to modifications in the activity of glucokinase. Thus, glucokinase could operate as an independent "hepatic sensor" of plasma glucose, directing glucose fluxes towards increased or decreased EGP. We hypothesize that 1) impairment in the ability of hypoglycemia per se to stimulate EGP in DM1 contributes in part to severe hypoglycemia in DM 1 patients (especially on intensive insulin therapy); 2) recurrent iatrogenic hypoglycemia may contribute to this loss of autoregulation of EGP, suggesting that the defect is at least partially due to hepatic sensor impairment; and 3) activation of hepatic glucokinase by catalytic amounts of fructose may sensitize the hepatic sensory mechanism to hypoglycemia in DM1 and thus restore glucose-induced activation of EGP.